US4859602A - Process for the preparation of stereoisomers of 1-aminoalkylphosphonic and phosphinic acids - Google Patents

Process for the preparation of stereoisomers of 1-aminoalkylphosphonic and phosphinic acids Download PDF

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US4859602A
US4859602A US06/774,140 US77414085A US4859602A US 4859602 A US4859602 A US 4859602A US 77414085 A US77414085 A US 77414085A US 4859602 A US4859602 A US 4859602A
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acid
acids
resolution
aminoalkylphosphonic
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Gerd Zimmermann
Josef Maier
Manfred Gloger
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Roche Diagnostics GmbH
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
    • C12P41/007—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures by reactions involving acyl derivatives of racemic amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
    • C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
    • C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N11/00—Carrier-bound or immobilised enzymes; Carrier-bound or immobilised microbial cells; Preparation thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • C12N9/80—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
    • C12N9/84—Penicillin amidase (3.5.1.11)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/001—Amines; Imines

Definitions

  • the present invention is concerned with a process for the preparation of stereoisomers of 1-aminoalkylphosphonic acids and of 1-aminoalkylphosphonic acids.
  • Peptide-like derivatives of 1-aminoalkylphosphonic acids and also of 1-aminoalkylphosphonic acids possess antibacterial effectiveness with regard to gram-positive and gram-negative micro-organisms and potentiate the activity of antibiotics, for example of penicillins, cephalosporins and D-cycloserine.
  • antibiotics for example of penicillins, cephalosporins and D-cycloserine.
  • alaphosphalin a dipeptide of L-alanine and L-aminoethylphosphonic acid, is of especial importance.
  • the derivatives of 1-aminoalkylphosphonic acids and of 1-aminoalkylphosphinic acids derived from the pure stereoisomeric forms and especially the derivatives derived from the L-form thereby show, in general, the greater biological activity (cf. Federal Republic of Germany Patent Specification No. 26 02 183; F. R. Atherton et al., Antimicrobial Agents and Chemotherapy, 15, May, 1979, p. 677).
  • optically-active forms of the L-aminoalkylphosphonic and -phosphinic acids can be prepared by chemical racemate resolution or by asymmetrical synthesis from optically-active precursors (cf. P. Kafarski et al., Can. J. Chem., 61, 2425/1983; J. W. Huber et al., Tetrahedron Letters, 33, 3049/1979; A. Vasella and R. Veffray, Helv. Chim. Acta, 65, 1983/1982).
  • This object can be achieved by carrying out the enzymatic resolution of the racemic N-acyl derivatives of 1-aminoalkylphosphonic acid and -phosphinic acids with a penicillin G-amidase (penicillin G-acylase).
  • N-acetyl derivatives but also other N-acyl derivatives of 1-aminoalkylphosphonic and -phosphinic acids can be stereoselectively resolved with very high rates of resolution and high optical purity.
  • the rates of resolution can be influenced by appropriate choice of the N-acyl radicals.
  • the process according to the present invention displays a very broad substrate specificity with regard to the N-acyl-R,S-1-aminoalkylphosphonic and -phosphinic acids.
  • the resolution activity decreases with increasing number of carbon atoms (chain length) of the 1-aminoalkylphosphonic acids and -phosphinic acids; in particular, the resolution activity and rate of resolution depend, however, upon the nature of the substituents on the 1-amino group, i.e. thus upon the nature of the acyl radical.
  • 1-acetaminoethylphosphonic acid is reacted with a specific activity of 0.5 U/g.
  • 1-phenylacetaminoethylphosphonic acid is reacted with a specific activity of 3000 U/g. Therefore, by appropriate choice of the N-acyl radical, it is possible to compensate for a decrease of the activity brought about by a higher number of carbon atoms in the aminoalkylphosphonic or -phosphinic acids.
  • Penicillin G-amidases used according to the present invention are enzymes which are able to split penicillin into 6-aminopenicillanic acid. They are formed by prokaryontric micro-organisms, such as especially by Escherichia coli (M. Cole et al., Meth. Enzym., 43, 698/1975) and are known under the EC No. 3.5.1.11. According to the present invention, penicillin G-amidase from E. coli, DSM 1900 (ATCC 11105) is especially preferred.
  • the penicillin G-amidase used according to the present invention can be employed as the free, watersoluble enzyme, for exampled as a lyophilisate, or also as immobilised enzyme in water-insoluble form.
  • the substrate concentrations are from 0.1 mol/liter to the limit of solubility in an aqueous or aqueous-organic reaction medium.
  • aqueous-organic reaction medium there can be used one which is conventional for enzyme reactions and especially one which, besides water, preferably contains an organic solvent which is readily miscible with or soluble in water, especially a lower alcohol, for example ethanol.
  • an aqueous reaction medium is preferably used.
  • the reaction temperature is preferably from 20° to 60° C., a temperature of 37° C., being especially preferred.
  • the period of reaction depends especially upon the enzyme activity, the enzyme and substrate concentration and the reaction temperature. As a rule, the reaction is carried out for a period of time of from 2 to 120 hours.
  • the enzyme used according to the present invention is sufficiently active at pH values of from about 5.0 to 8.5, the optimum pH value being 7. Therefore, it is preferable to operate at pH values of from 5.5 to 8.5 and especially at pH 7.
  • the reaction can thereby be carried out without or in the presence of an appropriate buffer, for example of a phosphate buffer.
  • the pH values are preferably controlled with an autotitration system.
  • the enzyme in immobilised form.
  • the reaction can then be carried out continuously in a reactor suitable for immobilised enzymes (for example a column reactor or a batch reactor; cf. for example D. H. Graf, Pharmazie in fer Zeit, 6, 43/1977), for example in a column process, or also discontinuously (batchwise).
  • immobilised enzyme there can be used, for example, carrier-bound penicillin G-amidase (Boehringer Mannheim GmBH).
  • the penicillin G-amidase is biologically and mechanically stable for several weeks and can, therefore, be used repeatedly in reactors; after 40 days (0.2 mole/liter of substrate solution: 37° C.), the loss of activity is ⁇ 5%.
  • reactors it is preferred to use batch reactors, for example stirrer vessel reactors, because, in the case of these reactors, an optimum pH control can easily be carried out.
  • the enzymatic resolution can be easily monitored analytically in known manner; the resolution of N-acetyl derivatives is preferably monitored by a discontinuous enzymatic acetate determination, whereas the resolution of other N-acyl derivatives, for example of chloroacetyl or phenylacetyl derivatives, is preferably carried out with the help of the known ninhydrin methods for the determination of free amino groups.
  • the stereoselective resolution can be detected via a polarimetric measurement of the isolated R-1-aminophosphonic acids or via a 50% approximation of the conversion.
  • Technical reactors can be controlled via a fine measurement of the change of speed of rotation in the reaction solution.
  • reaction mixtures of the enzymatic resolution can be done, for example, according to the following two methods:
  • reaction mixture acidified with acetic acid is evaporated and the S-1-acylaminoalkylphosphonic acid and the carboxylic acid liberated by enzymatic hydrolysis of the acyl radical is extracted with ethanol. As residue, there remains the R-1-aminoalkylphosphonic acid which is insoluble in ethanol.
  • the resolution bath is chromatographed on a strongly acidic ion exchanger in the H + -form. Using water as elution agent, there are thereby successively eluted the S-1-acylaminoalkylphosponic acid, together with the carboxylic acid of the acyl residue, and subsequently the R-1-aminoalkylphosphonic acid in pure form.
  • the carboxylic acid of the acyl residue can be separated from the S-1-acylaminoalkylphosphinic acid by simple extraction with organic solvents. As a rule, the phosphonic acid remains in the aqueous phase and can be isolated by evaporation.
  • the N-acylated S-1-aminoalkylphosphonic acid is deacylated, for example, by boiling with 6 mol/l aqueous hydrochloric acid.
  • the aminophosphonic acid is isolated in known manner by treatment of the solution of the hydrochloride in ethanol with propylene oxide or by chromatography on a strongly acid ion exchanger in the H + -form.
  • the R- and S-isomers of the 1-aminoalkylphosphonic acids and 1-aminoalkylphosphinic acids are, by means of the process according to the present invention, obtained with a high optical purity (>95%).
  • the process according to the present invention is especially suitable for the preparation of stereoisomers of 1-aminoalkylphosphonic acids of the general formula: ##STR1## wherein R 2 is a branched or preferably straight-chained alkyl radical containing up to 6 and especially up to 4 carbon atoms, which can optionally also be substituted, for example, by halogen, hydroxyl, alkoxy with up to 3 carbon atoms, phenyl and/or phenoxy, or R 2 is a phenyl radical.
  • R 2 can therefore, be, for example, methyl, hydroxymethyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl, phenyl or benzyl.
  • R 2 can have the same meaning.
  • the acyl radical R 1 --CO-- is especially one in which R 1 is a branched or preferably straight-chained alkyl radical with up to 6 carbon atoms, which can possibly be substituted by halogen, hydroxy, alkoxy with up to 3 carbon atoms, phenyl, phenoxy and/or thienyl, whereby a phenyl or phenoxy radical can also be substituted, for example by alkyl with up to 3 carbon atoms, hydroxyl, nitro, amino, halogen and/or alkoxy with up to 3 carbon atoms.
  • the radical R 1 can be, for example, methyl, butyl, chloromethyl, benzyl, phenoxymethyl, 2-methylbenzyl, 4-nitrobenzyl, 4-hydroxybenzyl, 4-aminobenzyl, thienyl-(2)-, 4-chlorobenzyl or 4-methoxybenzyl.
  • the 1-acylaminoalkylphosphonic acids used as starting materials can be prepared by methods known from peptide chemistry by the reaction of appropriate 1-aminoalkylphosphonic acids with activated carboxylic acid derivatives or carboxylic acids in the presence of a condensation agent.
  • the 1-acylaminoalkylphosphinic acids are obtainable in an analogous manner.
  • activated carboxylic acid derivatives there can be used, for example, acid chlorides, symmetrical anhydrides or mixed anhydrides with carbonic acid monoalkyl esters, active esters, for example p-nitrophenyl esters, 2,4,5-trichlorophenyl esters, N-hydroxysuccinimide or 1-N-hydroxybenzotriazole esters.
  • condensation agents there are mainly used carbodiimides, for example dicyclohexylcarbodiimide and N,N'-carbonyldiimidazole.
  • the amino group of the zwitterionic 1-aminoalkylphosphonic acid is preferably liberated by neutralisation of the phosphonic acid group with an alkali metal base, for example sodium hydroxide, or with a tertiary amine base, for example triethylamine.
  • an alkali metal base for example sodium hydroxide
  • a tertiary amine base for example triethylamine.
  • the aminoalkylphosphonic acids can also be acylated in the form of their alkyl esters or trialkylsilyl esters with an activated carboxylic acids.
  • the phosphonic acid alkyl esters can be split according to known methods by reaction with hydrobromic acid in glacial acetic acid or trimethyliodo- or bromosilane or trimethylchlorosilane/sodium iodide.
  • Trialkylsilyl esters are hydrolysed very simply by water.
  • the acylation reaction can be carried out in water, in a water/alcohol mixture or in an inert organic solvent, for example methylene chloride, acetone, acetonitrile, tetrahydrofuran, dimethylformamide or the like.
  • an inert organic solvent for example methylene chloride, acetone, acetonitrile, tetrahydrofuran, dimethylformamide or the like.
  • phosphinic acid derivatives for example methylene chloride, acetone, acetonitrile, tetrahydrofuran, dimethylformamide or the like.
  • racemic 1-aminoalkylphosphonic acids and -phosphinic acids are known or can be prepared by known processes (cf., for example, Synthesis, 883/1977; 479/1978; Pol. J. Chem., 52, 2271/1978).
  • the 1-acylaminoalkylphosphonic acids set out in the following Table 1 are prepared in an analogous manner. Some of the compounds are isolated from the acidic aqueous phase by extraction with ethyl acetate or by filtration over a strongly acidic ion exchanger in the H + -form (cf. remarks in Table 1).
  • R,S-1-amino-2-methylpropylphosphonic acid are dissolved in 30 ml. of water.
  • the pH of the solution is adjusted to 9 by the addition of 4 mol/l sodium hydroxide and 4.5 g. of acetic anhydride thereupon added dropwise.
  • the pH value is maintained at 9 by the addition of 4 mol/l sodium hydroxide.
  • the reaction solution is filtered over 300 ml. of strongly acidic ion exchanger (Dowex 50, H + -form), using water as the elution agent.
  • the product-containing fractions are evaporated and the residue is recrystallised from ethanol/diethyl ether. There is obtained 1.8 g. (73% of theory) R,S-1-acetamino-2-methylpropylphosphonic acid; m.p. 178°-180° C.
  • N-trimethylsilylaminoethylphosphonic acid bis-(trimethylsilyl) ester used as starting material is prepared by heating 3 g. 1-aminoethylphosphonic acid for 15 minutes with 9.4 ml. trimethylchlorosilane and 10.5 ml. triethylamine in 100 ml. methylene chloride. This solution is used directly for the acylation reaction.
  • 80 g. lyophilised, carrier-bound penicillin G amidase (Boehringer Mannheim GmBH) are vigorously stirred in 1 liter of weakly buffered 0.12 mole/liter substrate solution (TRAP 0.02 mole/liter; pH 7.0) at 37° C. for the period of the reaction, using a paddle stirrer, subsequently filtered off through a suction filter funnel, washed and lyophilised for further use.
  • FIG. 1 of the accompanying drawings shows the conversion/time diagram of the discontinuous resolution reaction.
  • the filtrate is further worked up in known manner (ion exchanger, extraction).
  • ion exchanger extraction
  • FIG. 2 of the accompanying drawings shows the course of the reaction (conversion/time diagram) of the discontinuous resolution reaction.
  • one third of the solution of a resolution batch from 250 g. R,S-1-phenylacetaminoethanephosphonic acid (resolution rate 98.2%) is acidified with 150 ml. glacial acetic acid.
  • the mixture is extracted with diethyl ether and the aqueous phase passed over 3 liters of strongly acidic ion exchanger (Dowex 50 in the H + -form).
  • the ion exchanger is eluted with water.
  • the first fraction (2.2 liters) contains acetic acid.
  • the second fraction (about 2 liters) there is present the S-1-phenylacetaminoethylphosphonic acid.

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US06/774,140 1984-09-25 1985-09-09 Process for the preparation of stereoisomers of 1-aminoalkylphosphonic and phosphinic acids Expired - Fee Related US4859602A (en)

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DE19843435156 DE3435156A1 (de) 1984-09-25 1984-09-25 Verfahren zur herstellung der stereoisomeren von 1-amino-alkylphosphonsaeuren oder 1-aminoalkylphosphinsaeuren

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5057607A (en) * 1990-06-08 1991-10-15 Eli Lilly And Company Enantiomerically selective biocatalyzed acylation
US5756346A (en) * 1989-02-06 1998-05-26 Hoechst Aktiengesellschaft Process for the enzymatic resolution of 2-amino-4-methyl-phosphinobutyric acid derivatives
US5766918A (en) * 1989-12-11 1998-06-16 Rhone-Poulenc Sante Enantioselective amidases and uses thereof
US6235727B1 (en) * 1998-07-16 2001-05-22 Aventis Pharma Deutschland Gmbh Sulfonylaminophosphinic and sulfonylaminophosphinic acid derivatives, methods for their preparation and use
EP1988078A1 (en) * 1996-05-01 2008-11-05 Ortho-McNeil Pharmaceutical, Inc. Carboxamide derivatives of pyrrolidine, piperidine and hexahydroazepine for the treatment of thrombosis disorders
US20110196014A1 (en) * 2008-08-01 2011-08-11 Bioxiness Pharmaceuticals, Inc. Methionine analogs and methods of using same

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DE3435156A1 (de) * 1984-09-25 1986-04-03 Boehringer Mannheim Gmbh, 6800 Mannheim Verfahren zur herstellung der stereoisomeren von 1-amino-alkylphosphonsaeuren oder 1-aminoalkylphosphinsaeuren
DE3516114A1 (de) * 1985-05-04 1986-11-06 Heiss, Bernhard R., 8000 München 1-acylamido-alkylphosphonsaeuren und ihre salze, verfahren zu deren herstellung und ihre verwendung als tenside
GB8728121D0 (en) * 1987-12-01 1988-01-06 Ciba Geigy Ag Resolution process
US5563127A (en) * 1993-03-24 1996-10-08 The Dupont Merck Pharmaceutical Company Boronic acid and ester inhibitors of thrombin
EP1315827A1 (en) 2000-09-08 2003-06-04 Dsm N.V. Method for the preparation of enantiomerically enriched amines
WO2002020821A2 (en) * 2000-09-08 2002-03-14 Dsm N.V. Process for the preparation of enantiomerically enriched amines

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5756346A (en) * 1989-02-06 1998-05-26 Hoechst Aktiengesellschaft Process for the enzymatic resolution of 2-amino-4-methyl-phosphinobutyric acid derivatives
US5756800A (en) * 1989-02-06 1998-05-26 Hoechst Aktiengesellschaft Process for the enzymatic resolution of 2-amino-4-methyl-phosphinobutyric acid derivatives
US5879930A (en) * 1989-02-06 1999-03-09 Hoechst Aktiengesellschaft Process for the enzymatic resolution of 2-amino-4-methyl-phosphinobutyric acid derivatives
US5766918A (en) * 1989-12-11 1998-06-16 Rhone-Poulenc Sante Enantioselective amidases and uses thereof
US5057607A (en) * 1990-06-08 1991-10-15 Eli Lilly And Company Enantiomerically selective biocatalyzed acylation
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JPS6188895A (ja) 1986-05-07
EP0176068A2 (de) 1986-04-02
DE3435156A1 (de) 1986-04-03
JPS6227800B2 (ja) 1987-06-16
EP0176068A3 (en) 1988-06-01
ATE61413T1 (de) 1991-03-15
DE3581994D1 (de) 1991-04-11
EP0176068B1 (de) 1991-03-06

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